Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In vitro studies indicate the therapeutic potential of mTOR inhibitors in treating multiple myeloma. To provide further support for this potential, we used the rapamycin analog CCI-779 in a myeloma xenograft model. CCI-779, given as 10 intraperitoneal injections, induced significant dose-dependent, antitumor responses against subcutaneous growth of 8226, OPM-2, and U266 cell lines. Effective doses of CCI-779 were associated with modest toxicity, inducing only transient thrombocytopenia and leukopenia. Immunohistochemical studies demonstrated the antitumor responses were associated with inhibited proliferation and angiogenesis, induction of apoptosis, and reduction in tumor cell size. Although CCI-779-mediated inhibition of the p70 mTOR substrate was equal in 8226 and OPM-2 tumor nodules, OPM-2 tumor growth was considerably more sensitive to inhibition of proliferation, angiogenesis, and induction of apoptosis. Furthermore, the OPM-2 tumors from treated mice were more likely to show down-regulated expression of cyclin D1 and c-myc and up-regulated p27 expression. Because earlier work suggested heightened AKT activity in OPM-2 tumors might induce hypersensitivity to mTOR inhibition, we directly tested this by stably transfecting a constitutively active AKT allele into U266 cells. The in vivo growth of the latter cells was remarkably more sensitive to CCI-779 than the growth of control U266 cells.
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PMID:In vivo antitumor effects of the mTOR inhibitor CCI-779 against human multiple myeloma cells in a xenograft model. 1530 93

Multiple myeloma is associated with a susceptibility to bacterial infections, specifically for encapsulated organisms such as Streptococcus pneumoniae. However, severe bacterial infection as the initial presentation of this disease has been rarely reported. The most common presenting features are anemia, lytic lesions, hypercalcemia, and renal failure. We report two cases of pneumococcal bacteremia as the initial manifestation of an underlying multiple myeloma. The first case is of a 68-year-old woman with pneumococcal pneumonia and bacteremia, presenting with a white blood cell count of 900/microL and mild anemia. Further work-up disclosed monoclonal IgG kappa and 50% plasma cells in bone marrow. Her course was complicated by acute renal failure requiring hemodialysis. The second patient is a 57-year-old man presenting with acute pneumococcal meningitis and bacteremia. Due to prior bacterial epiglottitis, further work-up disclosed IgG lambda monoclonal spike and 40% plasma cells in bone marrow. Both cases responded to antibiotic therapy without complications. These two cases add to the few patients described in the literature with pneumococcemia as the first sign of multiple myeloma. Features that were common in most of these cases, and that should lead to a suspicion of myeloma in an otherwise asymptomatic patient, are S. pneumoniae bacteremia, leukopenia, mild anemia, history of prior bacterial infections, and indirect evidence of a paraproteinemia, such as increased total protein levels with low albumin.
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PMID:Pneumococcemia as the presenting feature of multiple myeloma. 1549 48

The proteasome inhibitor bortezomib has demonstrated clinical activity in patients with multiple myeloma (MM). Adverse events, including thrombocytopenia and peripheral neuropathy, have affected 30% to 60% of patients overall, and interrupted therapy in 10% to 20%. No prior toxicity data are available for Asian patients who have used bortezomib for MM. We used National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0, to review the clinical records of patients with an MM diagnosis from 25 centers in Korea. The included patients were treated with bortezomib alone or in combination with other agents, including thalidomide. Ninety-five MM patients were treated. The patients had a median age of 60 years (range, 42-77 years). The median number of previous treatments was 3 (range, 0-10), and 39% of the patients had been treated with 4 or more major classes of agents, including thalidomide (67%), and autologous stem cell transplantation (51%). Regimens included bortezomib only in 38 patients (40%), bortezomib plus dexamethasone in 34 patients (36%), and bortezomib plus a thalidomide-containing regimen in 23 patients (24%). The analysis of patient response to therapy revealed a complete response (CR) or a near-CR in 31 patients (33%) and a partial response in 30 patients (32%), for an objective response rate of 65% in 93 patients. The most common adverse events reported were thrombocytopenia (47%), sensory neuropathy (42%), anemia (31%), and leukopenia (31%). Thirteen patients (14%) stopped therapy because of adverse events (neuropathy, 8; infection, 4; diarrhea, 1). Neuropathy greater than grade 2 was more frequent in patients who received 4 or more prior therapy regimens (17/37) than in those who received 3 or fewer (14/58). In addition, therapy including thalidomide was significantly correlated with neuropathy of grades 1 to 3 (P = .001). We identified 6 therapy-related deaths (6%) within 20 days after the last dose of bortezomib. The causes of death were infection in 3 patients, disease progression in 2 patients, and suicide in 1 patient. The incidences of thrombocytopenia and neurotoxicity were similar; however, gastrointestinal toxicities were relatively low in Korean patients compared with those reported in Western studies. Significant neuropathy was associated with the number of prior regimens and combination with thalidomide. These findings provide useful information for clinicians and patients using bortezomib.
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PMID:A multicenter retrospective analysis of adverse events in Korean patients using bortezomib for multiple myeloma. 1675 29

Thalidomide has direct antimyeloma and immunomodulatory effects. In addition, both thalidomide and metronomic chemotherapy inhibit angiogenesis. The synergy of such a combination may decrease toxicity while maintaining efficacy. The Hoosier Oncology Group conducted a phase II trial of oral cyclophosphamide (50 mg b.i.d. for 21 days), thalidomide (200 mg/day), and prednisone (50 mg q.o.d.) (CTP) per 28-day course in patients with relapsed multiple myeloma (MM). Of the 37 patients enrolled, 16 had prior stem cell transplantation. The median follow-up time was 25.3 months (95% confidence interval [CI] 23.2-27.7). Of 35 patients treated, 22 patients (62.9%) responded: 7 (20.0%) complete responses, 2 (5.7%) near-complete responses, and 13 (37.1%) partial responses. Eight patients (22.9%) had stable disease, and three (8.6%) had disease progression. Two patients withdrew from the study early due to reasons unrelated to progression or toxicity and were treated as nonresponders. The median time to best response and time to progression were 3.6 months (95% CI 2.8-10.9) and 13.2 months (95% CI 9.4-21.0), respectively. The median number of treatment cycles was seven (range 1-12 cycles). Grade III to IV toxicities included leukopenia (42.9%; febrile neutropenia, 11.4%), hyperglycemia (20%), sensory neuropathy (11.4%), thromboses (8%), and motor neuropathy (5.7%). No patient withdrew from the study due to toxicity. The efficacy and low toxicity of the CTP regimen support the future development of such an approach in MM.
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PMID:Final report of toxicity and efficacy of a phase II study of oral cyclophosphamide, thalidomide, and prednisone for patients with relapsed or refractory multiple myeloma: A Hoosier Oncology Group Trial, HEM01-21. 1722 4

We report the results of a non-randomized phase II study of low-dose thalidomide plus low-dose dexamethasone therapy in 66 patients with refractory multiple myeloma. The overall response rate (near complete, partial and minimal response) was 63.6%, and progression-free and overall survival periods were 6.2 and 25.4 months. In adverse events, the incidence of peripheral neuropathy and deep vein thrombosis was lower than the data reported in USA and Europe. On the other hand, leukopenia was observed in 41% of patients, including 11% of those with Grade 3. Leukopenia was closely related to pretreatment pancytopenia, especially thrombocytopenia. The incidence of adverse events related to dexamethasone was low. In conclusion, low-dose thalidomide plus low-dose dexamethasone therapy was as effective as high-dose thalidomide plus high-dose dexamethasone therapy in patients with refractory multiple myeloma. Leukopenia is one of the most serious adverse events in Japanese patients, especially in patients with pretreatment pancytopenia.
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PMID:Low-dose thalidomide plus low-dose dexamethasone therapy in patients with refractory multiple myeloma. 1765 99

Human dendritic cells have distinct roles in the regulation of immunity. In this study we analysed the kinetics and the proportion of myeloid and plasmacytoid subsets of dendritic cells (DC) in peripheral blood of 15 patients with multiple myeloma (MM) before and during treatment that included autologous transplantation. Control group of 15 healthy volunteers was evaluated by using the same approaches. Flowcytometric determination of relative and absolute cell counts in unmanipulated peripheral blood was based on the expression of surface antigens CD83 and HLA-DR. Depending on the expression of CD11c or CD123, we divided these cells into CD11c+ dendritic cells type 1 (DC1) and CD123+ DC type 2 (DC2). Significant differences were found in initial relative counts of CD83+ cells and of the DC2 subtype between the group of controls and the group of patients before treatment. In absolute counts, there was a difference only in the DC2 subtype. After induction treatment (vincristine, doxorubicin, and dexamethasone), the mean percentage of CD83+ DC and the DC1 percentage were significantly higher than initially, but there was no significant difference in absolute counts. Administration of G-CSF again increased the total DC numbers. Intermediate DC counts were found in the apheresis products. After engraftment, we found the highest relative DC numbers, but absolute counts were not very high because of leukopenia. Within six months after transplantation, normal relative and absolute DC counts were found in patients. Untreated patients with MM have significantly lower relative numbers of peripheral blood DC in comparison with healthy volunteers. The highest number of total DC was found after engraftment. The DC1/DC2 ratio showed relative predominance of DC1 subtype and the lowest DC1/DC2 ratio was found in the apheresis products. DC counts comparable with those of healthy volunteers were found in patients six months after transplantation.
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PMID:Dendritic cell counts and their subsets during treatment of multiple myeloma. 1782 19

Hoechst is developing flavopiridol, a synthetic flavonoid based on an extract from an Indian plant, for the potential treatment of cancer. Flavopiridol, a cyclin-dependent kinase inhibitor, arrests cell division and causes apoptosis in non-small lung cancer cells [283660]. A phase II trial, in collaboration with the National Cancer Institute, has commenced at the University of Chicago Medical Center, which involves patients with high or intermediate-grade lymphoma or multiple myeloma [272937], [277372]. In ex vivo experiments with tumor cells from refractory chronic lymphoblastic leukemia, dose-dependent CDK2 inhibition associated with apoptotic changes was seen at concentrations greater than 100 nM of flavopiridol. In vitro pharmacokinetic studies have shown that flavopiridol undergoes hepatic biotransformation to its corresponding glucoronide by uridine diphosphate glucoronosyltransferases [283791]. Flavopiridol inhibits CDK with an IC50 value of 0.4 mM [285707]. Preclinical toxicology studies in rats and dogs demonstrated dose-related leukopenia and drug-related lesions in the thymus, spleen and bone marrow. The gastrointestinal and bone marrow toxicity was dose-limiting [178579]. Hoechst Marion Roussel expects to launch flavopiridol in the year 2001, with potential sales in excess of DM 750 million [288651].
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PMID:Flavopiridol Hoechst AG. 1846 38

Bortezomib is approved for the treatment of patients with relapsed or refractory multiple myeloma (MM), but only a few clinical studies for Japanese patients who were treated with bortezomib have been reported. We retrospectively analyzed 40 patients with relapsed or refractory MM who have received bortezomib at three collaborating centers in Miyagi prefecture in Japan. All the patients have been received bortezomib in combination with dexamethasone. Responses were determined using International Myeloma Working Group uniform response criteria. The overall response was observed in 30 patients (75%), including very good partial response in 8 patients (20%), and partial response in 22 patients (55%). The median time to disease progression was 8.7 months, and the median overall survival has not been reached. The factors affecting time to disease progression were International Staging System stage, serum beta2-microglobulin level, and number of treatment cycles. The most common grade 3 and 4 adverse events were thrombocytopenia (50%), peripheral neuropathy (25%), leukopenia (25%), and herpes zoster infection (25%). Thus, bortezomib is well tolerated and effective for Japanese patients with relapsed or refractory MM. Our results suggest that serum beta2-microglobulin level may be a marker of prognosis on bortezomib therapy for patients with relapsed or refractory MM although further studies are needed.
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PMID:A retrospective analysis of bortezomib therapy for Japanese patients with relapsed or refractory multiple myeloma: beta2-microglobulin associated with time to progression. 1929 99

To obtain approval from the Ministry of Health, Labor and Welfare of Japan, a phase II study was conducted to assess the pharmacokinetics and pharmacodynamics of thalidomide along with its efficacy and safety in Japanese patients with multiple myeloma. Between 2005 and 2006, 42 patients were enrolled, and 37 patients met eligibility criteria. Of the 37 patients, 3 were excluded from efficacy analysis because of short duration of thalidomide administration (<4 weeks). The overall response rate was 35.3% (12/34), including partial response of 14.7% (5/34) and minimal response of 20.6% (7/34). The adverse events observed in high frequency (>40%) were leukopenia, neutropenia, drowsiness, dry mouth, and constipation. Grade 3 neutropenia was observed in nine cases. Peripheral neuropathy and eruption were observed in about one-quarter of the patients. Deep vein thrombosis was not observed. At a single oral dose of thalidomide (100 mg), the C (max) was 1.68 +/- 0.41 microg/ml, T (max) was 4.54 +/- 1.71 h, T (1/2) was 4.86 +/- 0.44 h, and AUC was 15.87 +/- 3.05 microg h/ml. Low-dose thalidomide was an effective and tolerable treatment for Japanese patients with relapsed/refractory myeloma. Leukopenia and neutropenia were the most serious adverse events. The pharmacokinetics was similar to those observed in Caucasian patients.
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PMID:Phase II and pharmacokinetic study of thalidomide in Japanese patients with relapsed/refractory multiple myeloma. 1939 82

We investigated efficacy and toxicity of lenalidomide in 24 heavily pretreated myeloma patients with a median age of 59 years (range: 37-70) and relapse after allo-SCT. Lenalidomide was given at a dose of 15 mg (n=4), or 25 mg (n=20), orally once daily on day 1 to day 1 every 28 days, with (n=20) or without (n=4) DHAP. The median number of lenalidomide cycles was five (range: 2-17). Major side effects were leukopenia (grade 4: 4%, grade 3: 21% and grade 2: 17%) and thrombocytopenia (grade 3: 17% and grade 2: 29%); infectious complications were observed in 50%. Non-hematological toxicity consisted of muscle cramps (n=9), fatigue (n=5) and constipation (n=2). Mild grade I-II GVHD was seen in three patients. Response was achieved in 66%: CR in 8%, VGPR in 8%, PR in 50% and SD in 13%. The median time to progression was 9.7 months (95% confidence interval (CI): 7.5-11.9), and median OS was 19.9 months (95% CI: 17.3-22.5). Immunomonitoring after lenalidomide showed significant increase of activated NK (NKp44(+)) and T (HLA-DR(+)) cells, as well as regulatory T cells (CD4(+), CD25(+), CD127(lo)), supporting an immunomodulating anti-myeloma effect of lenalidomide.
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PMID:Lenalidomide as salvage therapy after allo-SCT for multiple myeloma is effective and leads to an increase of activated NK (NKp44(+)) and T (HLA-DR(+)) cells. 1958 25


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